While the percentage of US adults who smoke tobacco has been declining in recent years, smoking continues to be a leading cause of preventable death and disease worldwide. Further, nicotine administration via alternative delivery systems has increased in recent years. Chronic use of nicotine induces neuroadaptations that contribute to withdrawal symptoms upon cessation of use. The severity of withdrawal symptoms in the first week of abstinence has been associated with increased vulnerability to relapse. The goal of this proposal is 1) to demonstrate that behavioral expression nicotine withdrawal-induced aversion can be modulated through, and is dependent upon, the IPN-LDTg-VTA pathway, and 2) to identify neuroadaptations within this circuitry induced by chronic nicotine that mediate affective withdrawal. The ultimate objective is to identify novel therapeutic approaches to reduce affective nicotine withdrawal symptoms to improve success during quit attempts.